“Atypical Manifestations of Celiac Disease,” was prepared by Rose Healy, a Physician Assistant at Franklin Square Medical Center in Baltimore. The article appeared in that Advance Health Care Network and was intended for an audience of Nurse Practitioners and Physicians’ Assistants.

The content is dense but I have faith in my pro-active, often self-educated gluten-free cohort. The article offers a comprehensive overview of the disease, co-morbitidies, diet and ongoing after care as well as a well-annotated directory to allow for additional explorations. Focus points have been bolded throughout by The Celiac Scene, for the ease of the reader.

Gluten-free products, gluten-free diets (GFDs) and celiac disease have been gaining more attention in recent years. Gluten-free food products are now widely available, and most consumers understand gluten to be potentially detrimental to health in some people. However, the majority of people may have misconceptions about celiac disease. They may not be aware of the typical and atypical signs and symptoms of celiac disease, nor the screening tests for it.

Gluten is found in wheat, rye and barley.1 Celiac disease is a chronic, immune-mediated inflammatory multi-system disorder with an inflammatory response to ingested gluten and gluten-related protein that presents with a variety of symptoms. The only known treatment is a GFD.1 Celiac disease can result from genetic, environmental and immunological factors.2

Worldwide prevalence of celiac disease is currently estimated at 1%.1 Celiac disease symptoms can arise from abnormalities across many body systems, but the typical presentation involves the gastrointestinal system and includes distended abdomen, low muscle mass, diarrhea, malabsorption, and failure to thrive.1

Early diagnosis of children with celiac disease can result in improved health-related quality of life. Therefore, education about manifestations, complications and screening information can lead to earlier diagnosis and treatment, better health-related quality of life, and better overall health outcomes.1,3

The typical symptoms of celiac disease involve the gastrointestinal tract, but recent literature discusses a widening variety of atypical and extraintestinal manifestations, such as refractory iron deficiency anemia, osteoporosis, short stature and pubertal delay, to name a few.4

Dermatitis herpetiformis is a dermatologic manifestation that develops in 15% to 25% of patients with celiac disease.4 This pruritic vesicular rash develops anywhere on the body and can be treated with a GFD.4 Evidence shows that celiac disease patients with dermatitis herpetiformis are at increased risk for non-Hodgkin lymphoma, especially those who do not adhere to a GFD.5

Osteomalacia and osteoporosis have been linked to celiac disease for factors such as secondary hyperparathyroidism due to vitamin D deficiency and systemic inflammation.4 Strict lifelong GFD, and possibly vitamin D and calcium supplements, can help recover normal bone density when celiac disease diagnosis is made in childhood or adolescence.6 The earlier children start treatment with GFD, the better chance they have of regaining normal bone mineral density.6

Celiac disease has been linked to a pulmonary condition called idiopathic pulmonary hemosiderosis, which mainly affects children and adolescents.4 The condition is characterized by repeated episodes of intra-alveolar bleeding that leads to abnormal accumulation of iron.

The most common hepatic presentation of celiac disease is isolated hypertransaminasemia with nonspecific histological changes in liver biopsy. This condition is associated with younger age, and levels have been shown to normalize with GFD.4

Celiac disease has also been linked with autoimmune hepatitis, primary biliary cirrhosis and primary sclerosing cholangitis.4 Liver damage in celiac disease can range from mild to severe, and it may be occur in 15% to 55% of celiac disease patients.7 Although the mechanism of liver abnormalities in celiac disease is unclear, a GFD is an effective treatment for celiac disease patients with liver disorders.7

The most common renal manifestation of celiac disease is glomerulonephritis. It is more prevalent in the celiac disease population compared to control populations.4

Celiac disease can affect the reproductive systems of both men and women. In women, celiac disease may cause delayed menarche or amenorrhea.4 In men, it may present with hypogonadism, erectile dysfunction, immature secondary sex characteristics, and reduced semen quality.4 Twenty-five percent of male celiac disease patients present with hyperprolactinemia, which leads to erectile dysfunction and loss of libido.4

Refractory iron deficiency anemia is one of the leading atypical presentations of celiac disease.4 Celiac disease may also induce folate and vitamin B12 deficiency, with presenting signs of macrocytic anemia, leukopenia and thrombocytopenia.4

Celiac disease patients are 10 times more likely to have an autoimmune disorder compared to the general population, including conditions such as type 1 diabetes, thyroid disease, Sjogren syndrome, Addison disease, autoimmune liver disease, cardiomyopathy and neurological disorders possibly linked to the human leukocyte antigen (HLA).4 Specifically, the HLA major histocompatibility complex class II antigen DQ2 is present in 86% to 100% of celiac disease patients.2 Type 1 diabetes and thyroid disease are the most common autoimmune diseases associated with celiac disease.4

Patients with celiac disease may present with psychiatric disorders such as schizophrenia, major depression and generalized anxiety disorder, possibly due to reduced monoaminergic production and lower serotonin levels.4 Significantly lower serotonin metabolites have been found in the cerebrospinal fluid of patients with celiac disease.4

Common atypical neurological manifestations include peripheral neuropathy and cerebellar ataxia.4 Less common manifestations include occipital calcifications, seizures, headache and myopathy.4 Seven percent of new celiac disease cases were diagnosed based on atypical neurological symptoms, and 16% of patients with neurological symptoms had undiagnosed celiac disease.4

Sensorineural hearing loss may be another manifestation of celiac disease.8 In at least one study, the prevalence of sensorineural hearing loss in children with celiac disease was significantly higher (by 40.6%) compared to control subjects.8 Undiagnosed hearing loss could lead to decreased socioemotional and behavioral development later in life.8 The findings show that hearing loss was detected at lower frequencies, which may lead to speech discrimination disabilities, language regression and deceleration of multiple facets of child development.8

Screening
Insufficient data exist to justify mass celiac disease screening in the general population.9,10 However, research shows that children with symptomatic celiac disease diagnosed by mass screening have significantly improved health-related quality of life and increased GFD adherence.10 More studies are needed to evaluate the health-related benefits from mass screening in a larger population and to evaluate the cost-effectiveness of mass screening.10

Patients with conditions such as type 1 diabetes, autoimmune thyroid and liver diseases, and/or who have a first-degree relative with celiac disease, face a higher risk for celiac disease comorbidity.9 This means that screening is more beneficial in these populations, even if they are asymptomatic.9

SEE ALSO: Celiac Disease Update

Children with iron deficiency anemia that is refractory to treatment or who have growth retardation would also benefit from celiac disease screening.11 Other conditions with increased risk of celiac disease co-morbidity include Down syndrome, Turner syndrome, Williams syndrome and selective immunoglobulin A deficiency; screening should also be considered in these populations.12

Up to 8% of patients with type 1 diabetes have characteristic features of celiac disease on small intestinal biopsy: 4.1% to 8.1% of Down syndrome patients; 8.2% of Turner syndrome patients; 8.2% of Williams syndrome patients; and 1.7 to 7.7% of patients with selective IgA deficiency.13

Testing asymptomatic children who have any of the conditions listed previously should begin around age 3 years, as long as they have eaten a gluten-containing diet for at least 1 year before testing.13 Evidence shows that antibody tests are more reliable in predicting mucosal status in children with celiac disease before starting a GFD, so children must be eating gluten-containing foods before antibody screening and biopsy in order to get an accurate diagnostic result.14 High-risk patient populations mentioned could have a negative initial celiac disease screen result, but may produce a positive result on repeat testing.13 Therefore, asymptomatic patients in those populations should receive repeat testing.13 No data exists to recommend when to stop celiac disease screening in patients with type 1 diabetes, however, screening is not necessary when the patient is HLA-DQ2 and HLA-DQ8 negative.17

The initial testing for celiac disease includes measurement of IgA antibody to human recombinant tissue transglutaminase (TTG-IgA).13 This is the preferred single test for celiac disease detection in patients older than 2 years.13,17 The sensitivity and specificity of the TTG-IgA test is 95% in the diagnosis of untreated celiac disease.17

Guidelines from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the American College of Gastroenterology (ACG) recommend HLA genotyping in asymptomatic children with associated conditions and/or a first-degree relative with celiac disease, in addition to negative serology.15 Confirmation of celiac disease diagnosis requires intestinal biopsy in all cases; villous atrophy is the main histopathologic feature in celiac disease.13

However, ESPGHAN has stated that children who meet the following criteria may not need an intestinal biopsy for diagnosis: typical symptoms of celiac disease; TTg-IgA level >10 times the upper limit of normal confirmed with positive endomysial antibodies in a separate blood sample; and positive HLA-DQ2.17

Celiac disease diagnosis is definitive when symptoms resolve with a strict GFD in previously symptomatic patients who had histologic changes in small intestinal biopsy.13 Positive serology reverting to negative after strict GFD further supports celiac disease diagnosis.13 About 80% of celiac disease patients who follow a GFD for 6 to 12 months have negative serology, and more than 90% who follow a GFD for 5 years have negative serology.17

Barriers to Screening
Barriers to the relatively cheap serologic screening for celiac disease are an issue in high prevalence populations.16 An estimated 85% of people with celiac disease are undiagnosed, and the average delay in diagnosis of symptomatic patients is 5.8 to 11 years.16 Common barriers are lack of knowledge about conditions that increase risk for celiac disease and not having a physician to order tests due to lack of insurance or lack of knowledge about where to get serologic testing.16

Barriers can be overcome with improved education of the general population and of healthcare providers about celiac disease symptoms, risk factors and serologic testing.16 One survey found that the top 10 most common reasons for not getting tested, in order of most common to least common, are: not knowing where to get tested; not knowing about celiac disease; not knowing risk factors; not having a physician to order tests; lack of motivation to get tested; thinking that the physician does not know what test to order; not knowing that screening tests are available; thinking that insurance does not cover costs; thinking that his or her physician will not offer treatment; and not wanting to see a physician for testing.16

Treatment
A strict GFD is the only treatment proven effective for all symptomatic children diagnosed with celiac disease, and they should start a GFD after diagnosis is confirmed by intestinal biopsy.1,13 Small amounts of gluten can lead to mucosal changes visible with intestinal biopsies, so a strict GFD must be taken seriously.13 Treatment with a GFD can reverse reduced bone mineralization in children, decrease risk for some intestinal cancers and lower associated mortality rates.13 Children should be monitored for symptoms, growth and adherence to a GFD. TTG should be measured after 6 months of treatment with GFD to check adherence.13

Patients diagnosed with celiac disease should be encouraged to have a TTG screen at 1-year intervals to check for GFD adherence.13 The ESPGHAN guidelines recommend that celiac disease serology be repeated every 3 years when HLA DQ2/DQ8 is positive.15 Additional biopsies are not recommended because evidence shows that 95% of children with celiac disease symptoms, characteristic biopsy and resolution of symptoms when following a GFD have celiac disease.13 Therefore, biopsies are unnecessary to monitor course of celiac disease.13

In addition, celiac disease patients who were vaccinated against hepatitis B before age 12 months had significantly lower response rates to the vaccine, with significantly lower anti-hepatitis B titers compared to control counterparts.2 Previous studies have reported lower response rates to hepatitis B vaccine in patients with celiac disease compared to healthy patients, therefore ordering anti-hepatitis B titers may be reasonable at the time of celiac disease diagnosis.2

Importance of EducationLapses in following a GFD are more common in patients with extra-intestinal symptoms and in patients with initially asymptomatic screen detection.3 Twelve percent of patients reported difficulty with adherence to GFD, and 82% of those specified difficulty due to lack of knowledge.3 The study concluded that physicians’ attitudes and counseling to patients upon diagnosis had a major impact on patients’ lives and perspective of celiac disease after 1 year of treatment.3 In addition, celiac disease patients with extra-intestinal symptoms experienced a more negative attitude about diagnosis compared to those with intestinal symptoms while following a GFD.3

For parents of children with celiac disease, food and feeding may become problem areas.12 Significant diet modification can change relationships and social habits, which can change identity development, especially of a child.12 Parents of children with celiac disease experience stress because they must pay attention to food contamination, which may cause anxiety and over-controlling attitudes related to feeding.12 Children with celiac disease rely on parents for GFD adherence; therefore, celiac disease education can strongly affect course, as well as the attitude of patients and their families.12

Conclusion
Celiac disease diagnosis is more difficult to make in children with an atypical presentation. If parents and primary care/pediatric providers were better informed of atypical manifestations and conditions that increase risk for celiac disease, children and adolescents with undiagnosed celiac disease would be more likely to get diagnosed at an early age and potentially avoid a multitude of possible symptoms and complications. Parents of children with celiac disease should understand that following a lifelong GFD is challenging, but they should be encouraged to view it as a superior alternative compared with lifelong use of medications or with untreated celiac disease that causes symptoms and complications. Parents and patients are more likely to adhere to a GFD and experience a more positive health-related quality of life if they are well informed by their primary care providers.

Rose Healy is a physician assistant at Franklin Square Medical Center in Baltimore.

References
1. Skjerning H, et al. Health-related quality of life in children and adolescents with celiac disease: patient-driven data from focus group interviews. Qual Life Res. 2014;23(6):1883-1894

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